ABSTRACT ? Overall Behavioral, emotional and cognitive disorders have been historically studied as diseases of the central nervous system (CNS). However, emerging data suggests a gut-brain connection in a variety of diseases that affect the brain. Our own data and others? suggests a gut-brain connection in Alzheimer?s disease (AD), a progressive neurodegenerative disorder that is the leading cause of dementia. There are currently no therapies to prevent or slow AD progression, causing a huge socioeconomic burden and highlighting our incomplete knowledge. Given an emerging role for gut microbiome and hypotheses implicating viral and bacterial contributions to AD pathogenesis, defining the bidirectional biochemical communication between the brain and the gut will improve understanding of neurodegenerative and psychiatric diseases. Indeed, it is crucial to study the brain not in isolation, but in the context of peripheral influences including diet, lifestyle, and microbiome. In this proposal we build on large initiatives and infrastructures co-established by our multi-disciplinary team including: The American Gut Project, The AD Metabolomics Consortium, Alzheimer?s Disease Research Centers (ADRCs), National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), The National Alzheimer?s Coordinating Center (NACC) and centers of excellence in informatics and systems biology. We aim to define the role of gut microbiome in AD pathogenesis and biochemical axis of communication between gut and brain. Aim 1: Examine the association between the gut microbiome and AD phenotypes. Aim 2: Define the biochemical axis of communication between the gut microbiome and the brain and identify metabolites that contribute to AD endophenotypes. Aim 3: Examine mechanistic links between the activity of the gut microbiome and AD pathogenesis, and identify new approaches for AD prevention that target the gut-brain axis. These aims will be enabled three projects supported by an Omics and Technology Core, a Computational and Systems Biology Core, and an Administrative Core that provides data and biorepository infrastructure. Project 1 will define changes in gut microbiome and metabolome across the AD trajectory; Project 2 leverages three existing clinical trials of controlled diets to examine dietary effects on gut microbiome, metabolome, cognition and brain imaging; Project 3 examines mechanism by defining gut- brain communication and microbiome-based interventions in animal models of AD. In this U19 we will create an unprecedented, high-quality dataset and resources specifically for the AD research community, and make these available under open science, FAIR (findable, accessible, interoperable, reusable) data principles. With our cross-disciplinary team of experts in clinical AD, gut microbiome research, imaging, metabolomics, informatics, deep learning and systems biology, this effort will yield novel biomarkers for AD progression and prognosis, and insight into mechanisms opening the door to development of transformative options for AD.